9-[(Substituted glycyl)amido]-6-(substituted)-5-hydroxy-6-deoxytetracyclines

Abstract: The invention provides compounds of the formula: wherein R, R¹, R² and W are defined in the specification. These compounds are useful as antibiotic agents.

Description: BACKGROUND OF THE INVENTION 1. Field of the Invention The invention relates to novel [4S-(4α,4aα, 5α,5aα,6α,12aα)]-4-(dimethylamino)-6-(substituted)-9-[[(substituted amino)substituted]amino]-1,4,4a,5,5a,-6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-1,11-dioxo-2-naphthacenecarboxamides herein after called 9-[(substituted glycyl)amido]-6-(substituted)-5-hydroxy-6-deoxytetracyclines, which exhibit antibiotic activity against a wide spectrum of organisms including organisms which are resistant to tetracyclines and are useful as antibiotic agents. The invention also relates to novel 9-[(haloacyl)amido]-6-(substituted)-5-hydroxy-6-deoxytetracycline and novel 9-[(protected aminoacyl)amido]-6-(substituted)-5-hydroxy-6-deoxytetracycline intermediates useful for making the novel compounds of the present invention and to novel methods for producing the novel compounds and intermediate compounds. SUMMARY OF THE INVENTION This invention is concerned with novel 9-[(substituted glycyl)amido]-6-(substituted)-5-hydroxy-6-deoxytetracyclines, represented by formula I, which have antibacterial activity; with methods of treating infectious diseases in warm blooded animals employing these new compounds; with pharmaceutical preparations containing these compounds; with novel intermediate compounds and processes for the production of these compounds. More particularly, this invention is concerned with compounds of formula I which have antibacterial activity against tetracycline resistant strains as well as a high level of activity against strains which are normally susceptible to tetracyclines. In formula I, R is selected from α-CH 3 ; R 1 is selected from hydrogen; straight or branched (C 1 -C 4 )alkyl group selected from methyl, ethyl, propyl and butyl; straight or branched (C 1 -C 4 )alkyl group optionally substituted with amino; (heterocyclo)methyl group said heterocycle selected from imidazolyl and 3-indolyl; (C 5 -C 6 )cycloalkylmethyl group selected from (cyclopentyl)methyl and (cyclohexyl) methyl; (C 2 -C 4 )carboxamidoalkyl group selected from carboxamidomethyl and carboxamidoethyl; R 2 is selected from hydrogen and (C 1 -C 2 )alkyl selected from methyl and ethyl; W is selected from amino; (C 1 -C 8 ) straight or branched alkyl monosubstituted amino group substitution selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, n-hexyl and n-octyl; (C 3 -C 6 )cycloalkyl monosubstituted amino group substitution selected from cyclopropyl, cyclopentyl and cyclohexyl; [(C 4 -C 5 )cycloalkyl] (C 1 -C 2 ) alkyl monosubstituted amino group substitution selected from (cyclopropyl)methyl and (cyclopropyl)ethyl; (C 3 -C 4 )alkenyl monosubstituted amino group substitution selected from allyl and 3-butenyl; (C 7 -C 10 )aralkylamino group selected from benzyl, 2-phenylethyl and 1-phenylethyl; straight or branched symmetrical disubstituted (C 2 -C 4 )alkylamino group substitution selected from dimethyl and diethyl; straight or branched unsymmetrical disubstituted (C 3 )alkylamino group substitution selected from methyl(ethyl); (C 2 -C 5 )azacycloalkyl group selected from pyrrolidinyl and piperidinyl; 1-azaoxacycloalkyl group selected from morpholinyl; substituted 1-azaoxacycloalkyl group selected from 2-(C 1 -C 3 )alkylmorpholinyl; [1,n]-diazacycloalkyl and substituted [1,n]-diazacycloalkyl group selected from piperazinyl, 2-(C 1 -C 3 )alkylpiperazinyl, 4-(C 1 -C 3 )alkylpiperazinyl, and 2,5-diaza-5-methylbicyclo[2.2.1]hept-2-yl and the diastereomers and enantiomers of said [1,n]-diazacycloalkyl and substituted [1,n]-diazacycloalkyl group; 1-azathiacycloalkyl and substituted 1-azathiacycloalkyl group selected from thiomorpholinyl and 2-(C 1 -C 3 )alkylthiomorpholinyl; N-azolyl group selected from 1-imidazolyl; (heterocycle)methylamino group selected from 2- or 3-thienylmethylamino and 2-, 3- or 4-pyridylmethylamino; (C 1 -C 4 )alkoxycarbonylamino group substitution selected from methoxycarbonylamino, ethoxycarbonylamino, and 1,1-dimethylethoxycarbonylamino; or R 1 and W taken together are -CH 2 CH 2 CH 2 NH-; and the pharmacologically acceptable organic and inorganic salts or metal complexes. It will be appreciated that when R 1 does not equal R 2 the stereochemistry of the asymmetric carbon (i.e. the carbon bearing the W substituent) may be either the racemate (DL) or the individual enantiomers (L or D). Also included in the present invention are compounds useful as intermediates for producing the above compounds of formula I. Such intermediate include those having the formula II: wherein: Y is selected from (CH 2 ) n X, n = 0-5, X is halogen selected from bromine, chlorine, fluorine and iodine; alternatively, X is a protected amino selected from trifluoroacetylamino, (C 1 -C 4 )alkoxycarbonylamino selected from t-butoxycarbonylamino, methoxycarbonylamino, ethoxycarbonylamino, allyloxycarbonylamino and 1,1,1-trichloroethoxycarbonylamino, (C 7 -C 14 )arylalkoxycarbonylamino selected from benzyloxycarbonylamino, naphthylmethoxycarbonylamino, 9-fluorenylmethoxycarbonylamino, p-methoxybenzyloxycarbonylamino, and p-nitrobenzyloxycarbonylamino, (C 7 -C 23 ) arylalkylamino selected from benzylamine, p-methoxybenzylamine, p-nitrobenzylamine, tritylamine and 4-methoxytritylamine; and R, R 1 and R 2 are as defined above. It will be appreciated that when R 1 does not equal R 2 the stereochemistry of the asymmetric carbon (i.e. the carbon bearing the W substituent) maybe be either the racemate (DL) or the individual enantiomers (L or D); and the pharmacologically acceptable organic and inorganic salts and metal complexes. Particularly preferred compounds are compounds according to the above formula II wherein: Y is selected from (CH 2 ) n X, n = 0-5, X is halogen selected from bromine, chlorine, fluorine and iodine; alternatively, X is a protected amino selected from trifluoroacetylamino, (C 3 -C 4 ) alkoxycarbonylamino selected from t-butoxycarbonylamino, allyloxycarbonylamino and 1,1,1-trichloroethoxycarbonylamino, (C 7 -C 14 )arylalkoxycarbonylamino selected from benzyloxycarbonylamino, and 9-fluorenylmethoxycarbonylamino], (C 7 -C 23 )arylalkylamino selected from benzylamine, and tritylamine; The invention also provides methods of producing the compounds of the invention, compositions comprising the compounds and their use as a medicament or in the preparation of a medicament for the treatment of bacterial infections in warm blooded animals. Suitable salts of the compounds of the invention include inorganic salts such as hydrochloric, hydrobromic, hydroiodic, phosphoric, nitric and sulfate salts and organic salts such as acetate, benzoate, citrate, systeine, fumarate and other amino acid salts. The novel compounds of the present invention may be readily prepared in accordance with the following schemes. The 9-[(substituted glycyl)amido]-6-(substituted)-5-hydroxy-6-deoxytetracyclines, or mineral acid salts, can be made by the procedure described in scheme I. In accordance with scheme I, 9-amino-6-(substituted)-5-hydroxy-6-deoxytetracycline or its mineral acid salt, 1 , is dissolved in a mixture of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)pyrimidone and acetonitrile or equivalent solvents. Sodium carbonate is added and the mixture is stirred for 5 minutes. An acid chloride, acid anhydride or suitably activated acylation reagent of the formula: wherein X=suitable leaving group and R 1 , R 2 , and W have been described hereinabove, is added and the reaction is stirred at room temperature for from 0.5-2 hours to give the corresponding 9-[(substituted glycyl)amido]-6-(substituted)-5-hydroxy-6-deoxytetracycline, or its mineral acid salt 3 . The second method for producing 9-[(substituted glycyl)amido]-6-(substituted)-5-hydroxy-6-deoxytetracyclines or its mineral acid salt 3 , is shown in scheme II. This method uses common intermediates which are easily prepared by reacting commercially available haloacyl halides, anhydrides or suitably activated haloacylating agents of the formula: wherein Y, R 1 and R 2 are as defined hereinabove and Q is halogen selected from bromine, chlorine, iodine, fluorine or suitable leaving group; with 9-amino-6-(substituted)-5-hydroxy-6-deoxytetracyclines, or its mineral acid salt 1 , to give straight or branched 9-[(haloacyl)amido]-6-(substituted)-5-hydroxy-6-deoxytetracyclines or its mineral acid salt, 2 , in almost quantitative yield. The above intermediates, straight or branched 9-[(haloacyl)amido]-6-(substituted)-5-hydroxy-6-deoxytetracyclines or its mineral acid salt 2 , react with a wide variety of nucleophiles, especially amines, having the formula WH, wherein W is as defined hereinabove to give the new 9-[(substituted glycyl)amido]-6-(substituted)-5-hydroxy-6-deoxytetracyclines or mineral acid salt 3 of the present invention. In accordance with Scheme II, 9-amino-6-(substituted)-5-hydroxy-6-deoxytetracycline or its mineral acid salt, 1 , is mixed with a) a polar-aprotic or protic (low temp.) solvent such as 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone, herein after called DMPU, hexamethylphosphoramide herein after called HMPA, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, 1,2-dimethoxyethane, water or equivalent thereof; b) an inert solvent such as acetonitrile, methylene chloride, tetrahydrofuran chloroform, carbon tetrachloride, 1,2-dichloroethane, tetrachloroethane, diethyl ether, t-butyl methyl ether, isopropyl ether or equivalent thereof; c) a base such as sodium carbonate, sodium bicarbonate, sodium acetate, potassium carbonate, potassium bicarbonate, triethylamine, cesium carbonate, lithium carbonate or bicarbonate equivalents; and d) a straight or branched haloacyl halide, anhydride or suitably activated haloacylating agent of the formula: wherein Y, R 1 , R 2 and Q are as defined hereinabove such as bromoacetyl bromide, (bromoacetic anhydride, chloroacetyl chloride (chloroacetic anhydride) or 2-bromopropionyl bromide or equivalent thereof; the halo, Y, and halide, Q, in the haloacyl halide can be the same or different halogen and is selected from bromine, chlorine, iodine and fluorine; Y is (CH 2 ) n X, n= 0-5, X is halogen; e) for 0.5 to 5 hours at room temperature to the reflux temperature of the reaction; to form the corresponding 9-[(haloacyl)amido]-6-(substituted)-5-hydroxy-6-deoxytetracycline, 2 , or its mineral acid salt. The intermediate, 9-[(haloacyl)amido]-6-(substituted)-5-hydroxy-6-deoxytetracycline or mineral acid salt 2 , is treated, under an inert atmosphere of helium, argon or nitrogen, with a) a nucleophile WH such as an amine or substituted amine or equivalent for example methylamine, dimethylamine, ethylamine, n-butylamine, propylamine or n-hexylamine; b) a polar-aprotic or protic solvent such as DMPU, HMPA, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, 1,2-dimethoxyethane, water or equivalent; c) for from 0.5 - 2 hours at room temperature or under reflux temperature to produce the desired 9-[(substituted glycyl)amido]-6-(substituted)-5-hydroxy-6-deoxytetracycline, 3 , or its mineral acid salt. Alternatively, the intermediate, 9-[(protected aminoacyl)amido]-6-(substituted)-5-hydroxy-6-deoxytetracycline (Y=protected amino group), is treated under an inert atmosphere of helium, argon or nitrogen with an appropriate nitrogen deprotection reagent using methods known to those skilled in the art [(a) Richard C. Larock, Comprehensive Organic Transformations, VCH Publishers, 1989; (b) Theodora Greene, Protecting Groups in Organic Synthesis, Academic Press, 1991]. It is well known to one skilled in the art that the appropriate nitrogen protection and deprotection scheme is chosen based on chemical and physical stability. In accordance with Scheme III, compounds of formula 3 are N-alkylated in the presence of formaldehyde and either a primary amine such as methylamine, ethylamine, benzylamine, methyl glycinate, (L or D)alanine, (L or D)lysine or their substituted congeners; or a secondary amine such as morpholine, pyrrolidine, piperidine or their substituted congeners to give the corresponding Mannich base adduct, 4 . The 9-[(substituted glycyl)amido]-6-(substituted)-5-hydroxy-6-deoxytetracyclines may be obtained as metal complexes such as aluminum, calcium, iron, magnesium, manganese and complex salts; inorganic and organic salts and corresponding Mannich base adducts using methods known to those skilled in the art (Richard C. Larock, Comprehensive Organic Transformations, VCH Publishers, 411-415, 1989). It is well known to one skilled in the art that an appropriate salt form is chosen based on physical and chemical stability, flowability, hygroscopicity and solubility. Preferably, the 9-[(substituted glycyl)amido]-6-(substituted)-5-hydroxy-6-deoxytetracyclines are obtained as inorganic salt such as hydrochloric, hydrobromic, hydroiodic, phosphoric, nitric or sulfate; or organic salt such as acetate, benzoate, citrate, cysteine or other amino acids, fumarate, glycolate, maleate, succinate, tartrate, alkylsulfonate or arylsulfonate. Depending on the stoichiometry of the acids used, the salt formation occurs with the C(4)-dimethylamino group (1 equivalent of acid) or with both the C(4)-dimethylamino group and the W group (2 equivalents of acid). The salts are preferred for oral and parenteral administration. Some of the compounds of the hereinbefore described Schemes have centers of asymmetry at the carbon bearing the W substituent. The compounds may, therefore, exist in at least two (2) stereoisomeric forms. The present invention encompasses the racemic mixture of stereo isomers as well as all stereoisomers of the compounds whether free from other stereoisomers or admixed with stereoisomers in any proportion of enantiomers. The absolute configuration of any compound may be determined by conventional X-ray crystallography. The stereochemistry centers on the tetracycline unit (i.e. C-4, C-4a, C-5, C-5a, C-6 and C-12a) remain intact throughout the reaction sequences. BIOLOGICAL ACTIVITY Method for in Vitro Antibacterial Evaluation (Table 1) The minimum inhibitory concentration (MIC), the lowest concentration of the antibiotic which inhibits growth to the test organism, is determined by the agar dilution method using Muller-Hinton II agar (Baltimore Biological Laboratories). An inoculum density of 1-5 x 10 5 CFU/ml and a range of antibiotic concentrations (32-0.004 pg/ml) is used. The plates are incubated for 18 hours at 35°C in a forced air incubator. The test organisms comprise strains that are sensitive to tetracycline and genetically defined strains that are resistant to tetracycline, due to inability to bind to bacterial ribosomes ( tet M) or by a tet K encoded membrane protein which confers tetracycline resistance by energy-dependent efflux of the antibiotic from the cell. Testing Results The claimed compounds exhibited good in vitro activity against a spectrum of doxycycline-sensitive and doxycycline-resistant Gram-positive and Gram-negative bacteria (Table 1). Notably, compounds A - D , compared to deoxycycline, exhibited excellent in vitro activity against strains containing the two major resistance determinants: efflux, as represented by tet B and tet D ( E. coli UBMS 88-1, E. coli MC4100 and E. coli J3272) and ribosomal protection, as represented by S. aureus UBMS 90-1 and UBMS 90-2 and E. coli UBMS 89-1 and 90-4. These compounds showed improved activity against Enterococcus and comparable activity to doxycycline against sensitive strains. Compounds E - F exhibited similar activity against deoxycycline-resistant, both efflux and ribosomal protection mechanisms, and deoxycycline-susceptible strains. Compounds G - H showed similar activity against doxycycline susceptible S. aureus strains and doxycycline-resistant (both efflux and ribosomal resistant) strains. Compounds I - J had similar activity against doxycycline-sensitive strains and strains resistant to doxycycline due to ribosomal protection, but were less effective against strains carrying the efflux ( tet K) resistance mechanism. As can be seen from Table 1, compounds of the invention can be used to prevent or control important mammalian and veterinary diseases such as diarrhea, urinary tract infections, infections of skin and skin structure, ear, nose and throat infections, wound infections, mastitis and the like. Thus, the improved efficacy of 9-[(N,N-dimethylglycyl)amido]-6-(substituted)-5-hydroxy-6-deoxytetracycline is demonstrated by the in vitro activity against isogenic strains into which the resistance determinants, such as tet M, are cloned (Table 1). LEGEND FOR COMPOUNDS Compound Name Doxycycline [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12, 12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide A [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-[[(dimethylamino)acetyl]amino]-1,4,4a, 5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide B [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-[(L-leucyl)amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide C [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-[(L-phenylalanyl)amino]-1,4,4a,5,5a,6, 11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide D [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-[(D-phenylalanyl)amino]-1,4,4a,5,5a,6, 11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide E [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-[[L-β-(cyclohexyl)alanyl]amino]-1,4,4a, 5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide F [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-[(L-prolyl)amino]-1,4,4a,5,5a,6,11, 12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide G [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-[(L-N,N-dimethylphenylalanyl)amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10, 12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide H [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-[(L-N-methylleucyl)amino]-1,4,4a,5,5a,6, 11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide I [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-[(L-tryptophanyl)amino]-1,4,4a,5,5a,6, 11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide J [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-[(L-tyrosyl)amino]-1,4,4a,5,5a,6, 11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide K [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-[(L-glutaminyl)amino]-1,4,4a,5,5a,6, 11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide L [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-[(glycyl)amino]-1,4,4a,5,5a,6,11,12aoctahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide M [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-[(bromoacetyl)amino]-1,4,4a,5,5a,6,11, 12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide (comparative example) N [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-[(L-lysyl)amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide When the compounds are employed as antibacterials, they can be combined with one or more pharmaceutically acceptable carriers, for example, solvents, diluents and the like, and may be administered orally in such forms as tablets, capsules, dispersible powders, granules, or suspensions containing, for example, from about 0.05 to 5% of suspending agent, syrups containing, for example, from about 10 to 50% of sugar, and elixirs containing for example, from about 20 to 50% ethanol and the like, or parenterally in the form of sterile injectable solutions or suspensions containing from about 0.05 to 5% suspending agent in an isotonic medium. Such pharmaceutical preparations may contain, for example, from about 25 to about 90% of the active ingredient in combination with the carrier, more usually between about 5% and 60% by weight. An effective amount of compound from 2.0 mg/kg of body weight to 100.0 mg/kg of body weight should be administered one to five times per day via any typical route of administration including but not limited to oral, parenteral (including subcutaneous, intravenous, intramuscular, intrasternal injection or infusion techniques), topical or rectal, in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy. These active compounds may be administered orally as well as by intravenous, intramuscular, or subcutaneous routes. Solid carriers include starch, lactose, dicalcium phosphate, microcrystalline cellulose, sucrose and kaolin, while liquid carriers include sterile water, polyethylene glycols, non-ionic surfactants and edible oils such as corn, peanut and sesame oils, as are appropriate to the nature of the active ingredient and the particular form of administration desired. Adjuvants customarily employed in the preparation of pharmaceutical compositions may be advantageously included, such as flavoring agents, coloring agents, preserving agents, and antioxidants, for example, vitamin E, ascorbic acid, BHT and BHA. The preferred pharmaceutical compositions from the standpoint of ease of preparation and administration are solid compositions, particularly tablets and hard-filled or liquid-filled capsules. Oral administration of the compounds is preferred. These active compounds may also be administered parenterally or intraperitoneally. Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in glycerol, liquid, polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserve against the contaminating action of micoorganisms such as bacterial and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oil. The invention will be more fully described in conjunction with the following specific examples which are not be construed as limiting the scope of the invention. Example 1 [4S-(4alpha,12aalpha)]-9-[(Bromoacetyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10, 12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide A stirred mixture of 0.030 g of 9-amino-5-hydroxy-6-deoxytetracycline, 0.10 g of sodium bicarbonate and 1 ml of N-methylpyrrolidinone at ambient temperature, is treated with 0.010 ml of bromoacetyl bromide. After 20 minutes, the suspension is filtered into stirred diethyl ether and the crude product is filtered. The crude product is purified by preparative HPLC to give 0.015 g of the desired product as a yellow glass. MS(FAB): m/z 579 (M+H) and 581 (M+H). 1 H NMR (CD 3 OH): δ 8.20(d,1H,J=8.3Hz,H-8); 6.90(d,1H, J=8.3Hz,H-7); 4.37(bs,1H,H-4); 4.08(s,2H,CH 2 Br); 3.52(dd,1H,J=8.25;11.40Hz,H-5); 2.92(bs,6H,NMe 2 ); 2.70-2.90(m,2H,H-4a and H-6); 2.51(dd,J=8.25;12.36Hz, H-5a) and 1.50(d,3H,J=6.7Hz,C-CH 3 ). Example 2 [4S-(4alpha,12aalpha)]-9-[(Bromoacetyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10, 12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide monohydrobromide To a room temperature solution of 1.75 g of 9-amino-5-hydroxy-6-deoxytetracycline monosulfate, 20 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone, hereinafter called DMPU, and 4 ml of acetonitrile is added 0.60 g of sodium carbonate. The mixture is stirred for 5 minutes followed by addition of 1.100 g of bromoacetyl bromide. The reaction is stirred one hour, filtered, and the filtrate added dropwise to a mixture of 50 ml of isopropanol and 500 ml of diethyl ether. The resulting yellow solid is collected, washed first with the mixed solvent (isopropanol and diethyl ether), followed by diethyl ether and dried to give 1.40 g of product. MS(FAB): m/z 579 (M+H) and 581 (M+H). Example 3 [4S-(4alpha,12aalpha)]-9-[(Chloroacetyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10, 12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide monohydrochloride To a room temperature solution of 0.05 g of 9-amino-5-hydroxy-6-deoxytetracycline hydrochloride, 1.5 ml of DMPU and 0.5 ml of acetonitrile is added 0.023 g of chloroacetyl chloride. The mixture is stirred for 30 minutes, then poured into a mixture of 0.5 ml of methyl alcohol, 2 ml of isopropyl alcohol and 20 ml of diethyl ether. The resulting solid is collected, washed with diethyl ether and dried to give 0.040 g of the desired product. MS(FAB): m/z 535 (M+H) and 537(M+H). Example 4 [4S-(4alpha,12aalpha)]-9-[(2-Bromo-1-oxopropyl)amino]-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide monohydrobromide The title compound is prepared by the procedure of Example 2, using 2.0 g of 9-amino-5-hydroxy-6-deoxytetracycline hydrochloride, 0.7 g of sodium carbonate, 20 ml of DMPU, 8 ml of acetonitrile and 1.73 g of 2-bromopropionyl bromide. The reaction is stirred for 1 hour to give 1.55 g of the desired product. This reaction works equally well without sodium carbonate. MS(FAB): m/z 593 (M+H) and 595 (M+H). Example 5 [7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2-naphthacenyl]-1-piperidineacetamide A solution of 0.108 g of product from Example 1, 1 ml of piperidine and 2 ml of N-methylpyrrolidone, under argon, is stirred at room temperature for 30 minutes. The reaction is concentrated in vacuo and the residue diluted with 1 ml of methanol. The solution is added dropwise to 100 ml of diethyl ether and the precipitate collected, washed with diethyl ether and dried to give a yellow product. The yellow solid is purified by preparative HPLC to give 0.045 g of the desired product as a yellow glass. MS(FAB): m/z 585 (M+H). 1 H NMR (CD 3 OH): δ 8.23(d,1H,J=8.3Hz,H-8); 6.95(d,1H, J=8.3Hz,H-7); 4.37(bs,1H,H-4); 4.13(s,2H,COCH 2 N); 3.52(dd,1H,J=8.25;11.40Hz,H-5); 2.92(bs,6H,NMe 2 ); 2.70-2.90(m,2H,H-4a and H-6); 2.51(dd,J=8.25;12.36Hz, H-5a); 2.3-2.55(m,4H); 1.70-1.99(m,6H) and 1.51(d,3H, J=6.7Hz,C-CH 3 ). Example 6 [7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2-naphthacenyl]-1-piperidineacetamide dihydrochloride A solution of 0.215 g of product from Example 1, 4 ml of piperidine and 4 ml of N-methylpyrrolidone, under argon, is stirred at room temperature for 30 minutes. The reaction is concentrated in vacuo and the residue diluted with 2 ml of methanol and added dropwise to 150 ml of diethyl ether. 2M hydrochloric acid in diethyl ether is added to give a yellow solid. The resulting solid is collected, washed with diethyl ether and dried to give 0.20 g of product. MS(FAB): m/z 585 (M+H). Substantially following the methods described in detail hereinabove, in Examples 5 or 6, the compounds of this invention listed below in Examples 7-22 are prepared. Example 24 General Procedure for the Preparation of Mannich Bases. A mixture of 0.5 mm of product from Example 23 (free base), 3 ml of t-butyl alcohol, 0.55 mm of 37% formaldehyde, and 0.55 mm of pyrrolidine, morpholine or piperidine is stirred at room temperature for 30 minutes followed by heating at 100°C for 15 minutes. The reaction mixture is cooled to room temperature and triturated with diethyl ether and hexane. The solid is collected, washed with diethyl ether and hexane, and dried to give the desired product. In this manner the following compound is made: [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-[[(t-butylamino)acetyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-N-(1-pyrrolidinylmethyl)-2-naphthacenecarboxamide Substantially following the method described in Example 5, the compounds of this invention listed below in Examples 25-48 are prepared using the product from Examples 1, 2 or 3. Example 25 [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-9-[[(methoxyamino)acetyl]amino]-1,11-dioxo-2-naphthacenecarboxamide Example 26 [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-9-[[[(phenylmethoxy) amino]acetyl]amino]-2-naphthacenecarboxamide Example 27 [7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2-naphthacenyl)-4-ethyl-1H-pyrazole-1-acetamide Example 28 [4S-(4alpha,12aalpha)]-9-[[(Cyclobutylmethylamino)-acetyl]amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide Example 29 [4S-(4alpha,12aalpha)]-9-[[(2-Butenylamino)acetyl]-amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxonaphthacenecarboxamide Example 30 [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-9-[[(hydroxyamino)acetyl]amino]-1,11-dioxo-2-naphthacenecarboxamide Example 31 [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-9-[[[methyl(phenylmethyl)-amino]acetyl]amino]-2-naphthacenecarboxamide Example 32 [7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2-naphthacenyl]-5-methyl-2,5-diazabicyclo[2.2.1]heptane-2-acetamide Example 33 [7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2-naphthacenyl]-3-methyl-4-morpholineacetamide Example 34 [7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2-naphthacenyl]-2-azabicyclo[2.2.1]heptane-2-acetamide Example 35 [7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2-naphthacenyl]-6-methyl-2-azabicyclo[2.2.2]octane-2-acetamide Example 36 [7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2-naphthacenyl]-4-methyl-1-piperazinecarboxamide Example 37 [7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2-naphthacenyl]-4-hydroxy-1-piperazineacetamide Example 38 [7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2-naphthacenyl]-3-methyl-1-piperazinecarboxamide Example 39 [7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2-naphthacenyl]-3-cyclopropyltetrahydro-4H-thiazine-4-acetamide Example 40 [7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2-naphthacenyl]-3-ethyl-1H-pyrrole-1-acetamide Example 41 [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-9-[[(1H-imidazol-2-ylmethylamino)-acetyl]amino]-1,11-dioxo-2-naphthacenecarboxamide Example 42 [7S-(7alpha,10aalpha)]-N-[2-[[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2-naphthacenyl]amino]-2-oxoethyl]alanine Example 43 [7S-(7alpha,10aalpha)]-N-[2-[[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2-naphthacenyl]amino]-2-oxoethyl]carbamic acid 1,1-di methyl ester Example 44 [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-9-[[[[(2-methylcyclopropyl)oxy]amino]-acetyl]amino]-1,11-dioxo-2-naphthacenecarboxamide Example 45 [4S-(4alpha,12aalpha)]-9-[[[(Bicyclo[2.2.2]oct-2-yloxy)amino]acetyl]amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide Example 46 [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-9-[[[(3-methyl-2-butenyl)amino]-acetyl]amino]-1,11-dioxo-2-naphthacenecarboxamide Example 47 [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-9-[[[[4-[(2-methyl-1-oxopropyl)-amino]phenyl]amino]acetyl]amino]-1,11-dioxo-2-naphthacenecarboxamide Example 48 [7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2-naphthacenyl]-3-ethyl-1-pyrrolidineacetamide Substantially following the method described in Example 5, the compounds of this invention listed below in Examples 49-55 are prepared using the product from Example 4. Example 49 [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-9-[[2-[[(1-methyl-1H-imidazol-2-yl)-methyl]amino]-1-oxopropyl]amino]-1,11-dioxo-2-naphthacenecarboxamide Example 50 [4S-(4alpha,12aalpha)]-9-[[2-(Dicyclopropylamino)-1-oxopropyl]amino]-4-(dimethylamino)-1,4,4a,5,5a,6,-11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide Example 51 [7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-10,12-dioxo-2-naphthacenyl]-4-methoxy-α-methyl-1-piperazinecarboxamide Example 52 [7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2-naphthacenyl]tetrahydro-α,2-dimethyl-4H-1,4-thiazine-4-acetamide Example 53 [7S-(7alpha,10aalpha)]-[2-[[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2-naphthacenyl]amino]-2-oxo-1-methylethyl]carbamic acid 2-propenyl ester Example 54 [7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2-naphthacenyl]-4-(aminomethyl)-α-methyl-1-piperidine acetamide Example 55 [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-9-[[2-[[3-(methylsulfonyl)phenyl]-amino]-1-oxopropyl]amino]-1,11-dioxo-2-naphthacenecarboxamide Substantially following the method, described in detail herein above in Example 2, the compound of invention Example 56 is prepared. Example 56 [4S-(4alpha,12aalpha)]-9-[(2-Bromo-2-methyl-1-oxopropyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,-12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide hydrobromide Example 57 [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-1,4,4a,5,5a,-6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-9-[[2-methyl-2-(methylamino)-1-oxopropyl]-amino]-1,11-dioxo-2-naphthacenecarboxamide The titled compound is prepared by the procedure of Example 5. The reactants are the product from Example 56 and methylamine. Example 58 [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-[[2-(dimethylamino)-2-methyl-1-oxopropyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide The titled compound is prepared by the procedure of Example 5. The reactants are the product from Example 56 and dimethylamine. Substantially following the method, described in detail herein above in Example 2, the compound of invention Example 59 is prepared. Example 59 [4S-(4alpha,12aalpha)]-9-[(2-Bromo-1-oxobutyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide hydrobromide Example 60 [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-1,4,4a,5,5a,-6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-9-[[(3-methylcyclobutyl)oxy]amino]-1-oxobutyl]-amino]-1,11-dioxo-2-naphthacenecarboxamide hydrobromide The titled compound is prepared by the procedure of Example 5. The reactants are the product from Example 59 and 3-methylcyclobutyloxyamine. Example 61 [4S-(4alpha,12aalpha)]-9-[[2-[(1,1-dimethylethyl)-methylamino]-1-oxobutyl]amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide The titled compound is prepared by the procedure of Example 5. The reactants are the product from Example 59 and N-methyl-t-butylamine. Example 62 [7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,20a,12-octahydro-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2-naphthacenyl]-α-ethyl-4-methyl-2-isoxazolidineacetamide The titled compound is prepared by the procedure of Example 5. The reactants are the product from Example 59 and 4-methyl-2-isoxazolidine. Example 63 [7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2-naphthacenyl]-α-ethyl-3-methyl-4H-1,2,4-triazole-4-acetamide The titled compound is prepared by the procedure of Example 5. The reactants are the product from Example 59 and 3-methyl-1,2,4-triazole. Substantially following the method, described in detail herein above in Example 2, the compound of invention Example 64 is prepared. Example 64 [4S-(4alpha,12aalpha)]-9-[(2-Bromo-1-oxopentyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide hydrobromide Example 65 [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-[[2-(dimethylamino)-1-oxopentyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide The titled compound is prepared by the procedure of Example 5. The reactants are the product from Example 64 and dimethylamine. Substantially following the method, described in detail herein above in Example 2, the compound of invention Example 66 is prepared. Example 66 [4S-(4alpha,12aalpha)]-9-[(2-Bromo-2-methyl-1-oxo butyl)amino]-4-dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide hydrobromide Example 67 [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-[[2-(ethylamino)-2-methyl-1-oxobutyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide The titled compound is prepared by the procedure of Example 5. The reactants are the product from Example 66 and ethylamine. Substantially following the method, described in detail hereinabove in Example 2, the compound of invention Example 68 is prepared. Example 68 [4S-(4alpha,12aalpha)]-9-[(2-Bromo-3-hydroxy-1-oxopropyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,-12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-2-naphthacenecarboxamide hydrobromide Example 69 [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-[[2-(dimethylamino)-3-hydroxy-1-oxopropyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide The titled compound is prepared by the procedure of Example 5. The reactants are the product from Example 68 and dimethylamine. Example 70 [7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2-naphthacenyl]-α-(hydroxymethyl)-4-methyl-1H-imidazole-1-acetamide The titled compound is prepared by the procedure of Example 5. The reactants are the product from Example 68 and 4-methylimidazole. Substantially following the method, described in detail herein above in Example 2, the compound of invention Example 71 is prepared. Example 71 [4S-(4alpha,12aalpha)]-9-[(2-Bromo-3-mercapto-1-oxopropyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,-12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide hydrobromide Example 72 [4S-(4alpha,12aalpha)]-9-[[2-(Diethylamino)-3-mercapto-1-oxopropyl]amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide The titled compound is prepared by the procedure of Example 5. The reactants are the product from Example 71 and diethylamine. Example 73 [7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,6,8,10a,11-pentahydroxy-5-methyl-10-12-dioxo-2-naphthacenyl]-α-(mercaptomethyl)-1-piperazineacetamide The titled compound is prepared by the procedure of Example 5. The reactants are the product from Example 71 and piperazine. Substantially following the method, described in detail herein above in Example 2, the compound of invention Example 74 is prepared. Example 74 [7S-(7alpha,10aalpha)]-4-[[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,6,8,10a,11-pentahydroxy-5-methyl-10-12-dioxo-2-naphthacenyl]amino]-3-bromo-4-oxobutanoic acid hydrobromide Example 75 [7S-(7alpha,10aalpha]-4-[[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2-naphthacenyl]amino]-3-(hexylamino)-4-oxobutanoic acid The titled compound is prepared by the procedure by Example 5. The reactants are the product from Example 74 and n-hexylamine. Example 76 [7S-(7alpha,10aalpha)]-4-[[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a-6,6a,7,10,10a,12-octahydro-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2-naphthacenyl]amino]tetrahydro-6-(hydroxymethyl)-2H-1,2-isoxazine-2-propanoic acid The titled compound is prepared by the procedure of Example 5. The reactants are the product from Example 74 and 6-(hydroxymethyl)-1,2-isoxazine. Example 77 [7S-(7alpha,10aalpha)]-4-[[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2-naphthacenyl]amino]-3-[ethyl(phenylmethyl)amino]-4-oxobutanoic acid The titled compound is prepared by the procedure of Example 5. The reactants are the product from Example 74 and N-ethylbenzylamine. Substantially following the method, described in detail herein above in Example 2, the compound of invention Example 78 is prepared. Example 78 [7S-(7alpha,10aalpha)]-5-[[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,6,8,10a-11-pentahydroxy-5-methyl-10,12-dioxo-2-naphthacenyl]amino]-4-bromo-5-oxopentanoic acid hydrobromide Example 79 [7S-(7alpha,10aalpha)]-5-[[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2-naphthacenyl]amino]-4-(cyclopropylamino)-5-oxopentanoic acid The titled compound is prepared by procedure of Example 5. The reactants are the product from Example 78 and cyclopropylamine. Substantially following the method, described in detail herein above in Example 2, the compound of invention Example 80 is prepared. Example 80 [4S-(4alpha,12aalpha)]-9-[(α-Bromophenylacetyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide hydrobromide Example 81 [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-[[2-(dimethylamino)-2-phenylacetyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1-11-dioxo-2-naphthacenecarboxamide The titled compound is prepared by the procedure of Example 5. The reactants are the product from Example 80 and dimethylamine. Substantially following the method, described in detail herein above in Example 2, the compound of invention Example 82 is prepared. Example 82 [4S-(4alpha,12aalpha)]-9-[[Bromo(4-hydroxyphenyl)-acetyl]amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide hydrobromide Example 83 [4S-(4alpha,12aalpha)]-9-[[(Butylamino)(4-hydroxyphenyl)acetyl]amino]-4-(dimethylamino)-1,4,4a,5,5a,-6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide The titled compound is prepared by the procedure of Example 5. The reactants are the product from Example 82 and n-butylamine. Substantially following the method, described in detail herein above in Example 2, the compound of invention Example 84 is prepared. Example 84 [4S-(4alpha,12aalpha)]-9-[[Bromo(4-methoxyphenyl)-acetyl]amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide hydrobromide Example 85 [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-[2-(dimethylamino)-2-(4-methoxyphenyl)acetyl]-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1-11-dioxo-2-naphthacenecarboxamide The titled compound is prepared by the procedure of Example 5. The reactants are the product from Example 84 and dimethylamine. Substantially following the method, described in detail herein above in Example 2, the compound of invention Example 86 is prepared. Example 86 [4S-(4alpha,12aalpha)]-9-[[Bromo[4-trifluoromethyl)-phenyl]acetyl]amino]-4-(dimethylamino)-1,4,4a,5,5a,6,-11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide hydrobromide Example 87 [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-[[2-(ethylmethylamino)-3-[4-(trifluoromethyl)phenyl]-acetyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide The titled compound is prepared by the procedure of Example 5. The reactants are the product from Example 86 and N-ethylmethylamine. Substantially following the method, described in detail herein above in Example 2, the compound of invention Example 88 is prepared. Example 88 [4S-(4alpha,12aalpha)]-9-[[Bromo[4-(dimethylamino)-phenyl]acetyl]amino]-4-(dimethylamino)-1,4,4a,5,5a,6,-11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide hydrobromide Example 89 [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-[[[4-(dimethylamino)phenyl](2-propenylamino)acetyl]-amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide The titled compound is prepared by the procedure of Example 5. The reactants are the product from Example 88 and N-allylamine. Example 90 [7S-(7alpha,10aalpha)]-N-[2-[[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2-naphthacenyl]amino]-2-oxoethyl]carbamic acid 1,1-dimethylethyl ester To a room temperature solution of 0.175 g of N-(tert-butoxycarbonyl)glycine in 5 ml of methylene chloride is added 0.91 g of dicyclohexylcarbodiimide. The reaction mixture is stirred for 30 minutes, filtered and concentrated in vacuo . The residue is dissolved in 2 ml of N-methylpyrrolidone and added to a solution of 0.142 g of 9-amino-5-hydroxy-6-deoxytetracycline in 2 ml of N-methylpyrrolidinone. After 2 hours, the solvent is concentrated in vacuo and the residue is purified by reverse phase chromatography to give 0.160 g of the desired product. MS(FAB): m/z 617 (M+H) 1 H NMR (CD 3 OH): δ 8.30(d,1H,J=8.1 Hz,H-8); 6.87(d,1H,H-7); 4.37(bs,1H,H-4), 4.18(s,2H,CH 2 CON-); 3.53(dd,1H,J=8.25 and 11.40 Hz,H-5); 2.93(bs,6H,N(CH 3 ) 2 ); 2.70-2.90(m,2H,H-4a and H-6); 2.51(dd,1H,J=8.25 and 12.36 Hz,H-5a); 1.96(s,9H,t-butyl); 1.50(d,3H,C(6)-CH 3 ). Example 91 [4S-(4alpha,12aalpha)]-9-[(Aminoacetyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide The product from Example 90 is dissolved in 4 ml of trifluoroacetic acid/anisole (9:1), stirred for 45 minutes and slowly poured into 150 ml of diethyl ether. The precipitate is collected and purified by reverse phase chromatography to give 0.10 g of the desired product as a gold glass. MS(FAB): m/z 517 (M+H). 1 H NMR (CD 3 OH): δ 8.24(d,1H,J=8.2 Hz,H-8); 6.92(d,1H,H-7); 4.35(bs,1H,H-4); 3.91(s,2H,CH 2 CON-); 3.52(dd,1H,J=8.24 and 11.40 Hz,H-5); 2.92(bs,6H,N(CH 3 ) 2 ); 2.70-2.90(m,2H,H-4a and H-6); 2.52(dd,1H,J=8.24 and 12.36 Hz,H-5a); 1.50(d,3H,C(6)-CH 3 ). Example 92 [4S-(4alpha,12aalpha)]-9-[L-(N-Methylleucyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide The title compound is prepared by the tandem procedure of Examples 90 and 91. N-(tert-butoxycarbonyl)-N-methyl-L-leucine is coupled with 9-amino-5-hydroxy-6-deoxytetracycline to give the protected intermediate which is then deprotected and purified to give the desired compound. MS(FAB): m/z 587 (M+H). 1 H NMR (CD 3 OH): δ 8.11(d,1H,J=8.2 Hz,H-8); 6.97(d,1H,H-7); 4.37(bs,1H,H-4); 4.08(dd,1H,C H CONH); 3.53(dd,1H,J=8.25 and 11.40 Hz,H-5); 2.94(bs,6H,NMe 2 ); 2.70-2.90(m,2H,H-4a and H-6); 2.71(s,3H,NCH 3 ); 2.51(dd,1H,J=8.25 and 12.36 Hz,H-5a); 1.52(d,3H, J=7.1 Hz, C(6)-CH 3 ); 1.5-1.6(m,3H,CH-CH 2 C); 0.90(d,6H,Me 2 CH). Example 93 [4S-(4alpha,12aalpha)-9-[(L-Glutamyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide The title compound is prepared by the tandem procedure of Example 90 and 91. tert-Butyl N-(tert-butoxycarbonyl)-γ-L-glutamate is coupled with 9-amino-5-hydroxy-6-deoxytetracycline to give the protected intermediate which is then deprotected and purified to give the desired compound. MS(FAB): m/z 589 (M+H). Example 94 [4S-(4alpha,12aalpha)-9-[(L-Aspartyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide The title compound is prepared by the tandem procedure of Example 90 and 91. tert-Butyl N-(tert-butoxycarbonyl)-β-L-aspartate is coupled with 9-amino-5-hydroxy-6-deoxytetracycline to give the protected intermediate which is then deprotected and purified to give the desired compound. MS(FAB): m/z 575 (M+H). Example 95 [4S-(4alpha,12aalpha)]-9-[(D-Phenylalanyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide To a room temperature solution of 0.40 g of N-(9-fluorenylmethoxycarbonyl)-D-phenylalanine in 20 ml of methylene chloride/tetrahydrofuran (1:1) is added 0.095 g of dicyclohexylcarbodiimide. The reaction mixture is stirred for 1 hour, filtered and concentrated in vacuo . The residue is added to a solution of 0.151 g 9-amino-5-hydroxy-6-deoxytetracycline in 3 ml of N-methylpyrrolidone and the mixture is stirred for 4 hours. One ml of piperidine is added and the mixture stirred for an additional 20 minutes. The reaction mixture is slowly poured into 150 ml of stirring diethyl ether and the resulting precipitate is collected. The light yellow powder is purified by preparative chromatography to give 0.049 g of the desired product as a dark yellow glass. MS(FAB): m/z 607 (M+H). 1 H NMR (CD 3 OH): δ 8.11(d,1H,J=6.9 Hz,H-8); 7.31(bs,5H,C 6 H 5 ); 6.92(d,1H,H-7); 4.40(t,1H,J=8.9 Hz, CHCO); 4.37(bs,1H,H-4); 3.53(dd,J=8.25 and 11.40 Hz, H-5); 3.15(d,2H,J=8.9 Hz,CH 2 CHO); 2.92(bs,6H,NMe 2 ); 2.70-2.90(m,2H,H-4a and H-6); 2.51(dd,1H,J=8.25 and 12.35 Hz,H-5a); and 1.50(d,3H,J=7.1 Hz, C(6)-CH 3 ). Example 96 [4S-(4alpha,12aalpha)]-9-[(L-Phenylalanyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide The title compound is prepared by the procedure of Example 92 using N-(9-fluorenylmethoxycarbonyl)-L-phenylalanine as the α-aminoacyl component. MS(FAB): m/z 607 (M+H). 1 H NMR (CD 3 OH): δ 8.11(d,1H,J=6.9 Hz,H-8); 7.31(bs,5H,C 6 H 5 ); 6.92(d,1H,H-7); 4.40(t,1H,J=8.9 Hz; CHCO); 4.37(bs,1H,H-4); 3.53(dd,J=8.25 and 11.40 Hz, H-5); 3.15(d,2H,J=8.9 Hz, CH 2 CHO); 2.92(bs,6H,NMe 2 ), 2.70-2.90(m,2H,H-4a and H-6); 2.51(dd,1H,J=8.25 and 12.35 Hz,H-5a); and 1.50(d,3H,J=7.1 Hz, C(6)-CH 3 ). Example 97 [4S-(4alpha,12aalpha)]-9-[[L-β-(Cyclohexyl)alanyl]-amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide The tile compound is prepared by the procedure of Example 92 using N-(9-fluorenylmethoxycarbonyl)-β-cyclohexyl-L-alanine as the α-aminoacyl component. MS(FAB): m/z 613 (M+H). Example 98 [4S-(4alpha,12aalpha)]-9-[(L-Leucyl)-amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide The tile compound is prepared by the procedure of Example 92 using N-(9-fluorenylmethoxycarbonyl)-L-leucine as the α-aminoacyl component. MS(FAB): m/z 573 (M+H). Example 99 [4S-(4alpha,12aalpha)-9-[(L-Glutaminyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide The tile compound is prepared by the procedure of Example 92 using N-(9-fluorenylmethoxycarbonyl)-L-glutamine as the α-aminoacyl component. MS(FAB): m/z 588 (M+H). Example 100 [4S-(4alpha,12aalpha)-9-[(L-Prolyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide The title compound is prepared by the procedure of Example 90 coupling L-proline with 9-amino-5-hydroxy-6-deoxytetracycline. MS(FAB): m/z 557 (M+H). Example 101 [4S-(4alpha,12aalpha)-9-[(L-(N,N-Dimethylphenylalanyl)-amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide The title compound is prepared by the procedure of Example 90 coupling L-(N,N-dimethyl)-phenylalanine with 9-amino-5-hydroxy-6-deoxytetracycline. MS(FAB): m/z 635 (M+H). Example 102 [4S-(4alpha,12aalpha)-9-[(L-Tyrosinyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide To a room temperature solution of 4.60 g of N-(9-fluorenylmethoxycarbonyl)-O-(tert-butyl)-L-tyrosine in 50 ml of methylene chloride/tetrahydrofuran (1:1) is added 1.04 g of dicyclohexylcarbodiimide. The reaction mixture is stirred for 1 hour, filtered and concentrated in vacuo . The residue is added to a solution of 2.30 g 9-amino-5-hydroxy-6-deoxytetracycline in 30 ml of N-methylpyrrolidone and the mixture is stirred for 4 hours. Five ml of piperidine is added, the mixture stirred for an additional 30 minutes and concentrated in vacuo . The residue is dissolved in 30 ml of trifluoroacetic acid/anisole (9:1), stirred for 45 minutes and slowly poured into 1000 ml of diethyl ether. The resulting precipitate is collected and purified by reverse phase chromatography to give 1.3 g of the desired product as a gold glass. MS(FAB): m/z 623 (M+H). Example 103 [4S-(4alpha,12aalpha)-9-[(L-Lysyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide The title compound is prepared by procedure of Example 102 using N α -(9-fluorenylmethoxycarbonyl)-N γ -(tert-butoxycarbonyl)-L-lysine and 9-amino-5-hydroxy-6-deoxytetracycline. MS(FAB): m/z 588 (M+H). Example 104 [4S-(4alpha,12aalpha)-9-[(L-Tryptophanyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide The titled compound is prepared by procedure of Example 102 using N α -(9-fluorenylmethoxycarbonyl)-N-trityl-L-tryptophan and 9-amino-5-hydroxy-6-deoxytetracycline. MS(FAB): m/z 646 (M+H).

Claims: A compound of the formula: wherein: R is α-CH 3 ; R 1 is selected from hydrogen; straight or branched (C 1 -C 4 ) alkyl group selected from methyl, ethyl, propyl and butyl; straight or branched (C 1 -C 4 ) alkyl group optionally substituted with amino; (heterocyclo)methyl group said heterocycle selected from imidazolyl and 3-indolyl; (C 5 -C 6 ) cycloalkylmethyl group selected from (cyclopentyl)methyl and (cyclohexyl) methyl; (C 2 -C 4 )carboxamidoalkyl group selected from carboxamidomethyl and carboxamidoethyl; R 2 is selected from hydrogen and (C 1 -C 2 ) alkyl selected from methyl and ethyl; W is selected from amino; (C 1 -C 8 ) straight or branched alkyl monosubstituted amino group substitution selected from methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, n-hexyl and n-octyl; (C 3 -C 6 ) cycloalkyl monosubstituted amino group substitution selected from cyclopropyl, cyclopentyl and cyclohexyl, [(C 4 -C 5 ) cycloalkyl] (C 1 -C 4 ) alkyl monosubstituted amino group substitution selected from (cyclopropyl)methyl and (cyclopropyl)ethyl; (C 3 -C 4 ) alkenyl monosubstituted amino group substitution selected from allyl and 3-butenyl; (C 7 -C 10 ) aralkylamino group selected from benzyl, 2-phenylethyl and 1-phenylethyl; straight or branched symmetrical disubstituted (C 2 -C 4 ) alkylamino group substitution selected from dimethyl and diethyl; straight or branched unsymmetrical disubstituted (C 3 ) alkylamino group substitution selected from methyl(ethyl);(C 2 -C 5 ) azacycloalkyl group selected from pyrrolidinyl and piperidinyl; 1-azaoxacycloalkyl group selected from morpholinyl; substituted 1-azaoxacyclo- alkyl group selected from 2-(C 1 -C 3 )alkylmorpholinyl; [1,n]-diazacycloalkyl and substituted [1,n]-diazacycloalkyl group selected from piperazinyl, 2-(C 1 -C 3 )alkyl- piperazinyl, 4-(C 1 -C 3 )alkylpiperazinyl, and 2,5-diaza-5-methylbicyclo[2.2.1]hept-2-yl and the diastereomers and enantiomers of said [1,n]-diazacycloalkyl and substituted [1,n]-diazacycloalkyl group; 1-azathiacycloalkyl and substituted 1-azathiacycloalkyl group selected from thiomorpholinyl and 2-(C 1 -C 3 )alkylthiomorpholinyl; N-azolyl group selected from 1-imidazolyl; (heterocycle)methylamino group selected from 2- or 3-thienylmethylamino and 2-, 3- or 4-pyridylmethylamino; (C 1 -C 4 )alkoxycarbonylamino group substitution selected from methoxycarbonylamino, ethoxycarbonylamino, and 1,1-dimethylethoxycarbonyl- amino; or R 1 and W taken together are -CH 2 CH 2 CH 2 NH-; and the pharmacologically acceptable organic and inorganic salts or metal complexes. A compound of the formula: wherein: Y is selected from (CH 2 ) n X, n = 0-5, X is halogen selected from bromine, chlorine, fluorine and iodine; alternatively, X is a protected amino selected from trifluoroacetylamino, (C 1 -C 4 ) alkoxycarbonylamino [selected from t-butoxycarbonylamino, methoxycarbonylamino, ethoxycarbonylamino, allyloxycarbonylamino and 1,1,1-trichloroethoxycarbonyl- amino], (C 7 -C 14 ) arylalkoxycarbonylamino selected from benzyloxycarbonylamino, naphthylmethoxycarbonylamino, 9-fluorenylmethoxycarbonylamino, p-methoxybenzyloxy- carbonylamino, and p-nitrobenzyloxycarbonylamino, (C 7 -C 23 ) arylalkylamino selected from benzylamine, p-methoxybenzylamine, p-nitrobenzylamine, tritylamine and 4-methoxytritylamine; R, R 1 and R 2 are as defined in Claim 1. The compound according to Claim 1 wherein said inorganic salts comprise: hydrochloric, hydrobromic, hydroiodic, phosphoric, nitric or sulfate; said organic salts comprise: acetate, benzoate, citrate, cysteine or other amino acid, fumarate, glycolate, maleate, succinate, tartrate, alkylsulfonate or arylsulfonate; and said metal complexes comprise: aluminum, calcium, iron, magnesium, manganese and complex salts. ; A compound according to Claim 1, [4S-(4alpha,12aalpha)]-4-(dimethylamino)-1,4,4a,5,5a, 6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6- methyl-9-[[(dimethylamino)acetyl]amino]-1,11-dioxo- 2-naphthacenecarboxamide; [4S-(4alpha, 12aalpha)]-4-(dimethylamino)-9- [[(dimethylamino)acetyl]amino]-1,4,4a,5,5a,6,11,12a- octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide monohydrochloride; [4S-(4alpha, 12aalpha)]-4-(dimethylamino)-1,4,4a,5,5a,-6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl- 1,11-dioxo-9-[[(dimethylamino)acetyl]amino]-2-naphthacenecarboxamide dihydrochloride; [7S-(7alpha,10aalpha)]-N-[9-(aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro- 1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2- naphthacenyl]-1-pyrrolidineacetamide; [7S-(7alpha,10aalpha)]-N-[9-(aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,6,8, 10a,11-pentahydroxy-5-methyl-10,12-dioxo-2-naphthacenyl]-1-piperidineacetamide; [4S-(4alpha,12aalpha)]-9-[[(butylamino)acetyl]amino]- 4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5, 10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide; [4S-(4alpha,12aalpha)]-4-(dimethylamino)-9-[[(diethylamino)acetyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide; [4S-(4alpha,12aalpha)]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl- 1,11-dioxo-9-[[(1,1-dimethylethylamino)acetyl]amino]- 2-naphthacenecarboxamide; [7S-(7alpha,10aalpha)]-N-[9-(aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,6,8, 10a,11-pentahydroxy-5-methyl-10,12-dioxo-2-naphthacenyl]-1-morpholineacetamide; [4S-(4alpha,12aalpha)]-4-(dimethylamino)-1,4,4a,5,5a,-6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl- 1,11-dioxo-9-[[[(phenylmethyl)amino]acetyl]amino]-2- naphthacenecarboxamide dihydrochloride; [4S-(4alpha,12aalpha)]-4-(dimethylamino)-1,4,4a,5,5a,- 6,11,12a-octahydro-3,5,10,12,12a-pentabydroxy-6-methyl-1,11-dioxo-9-[[[(2-thienylmethyl)amino]acetyl]amino]-2- naphthacenecarboxamide dihydrochloride; [4S-(4alpha,12aalpha)]-4-(dimethylamino)-1,4,4a,5,5a,-6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl- 9-[[[(2-methylpropyl)amino]acetyl]amino]-1,11-dioxo-2-naphthacenecarboxamide dihydrochloride; [4S-(4alpha,12aalpha)]-4-(dimethylamino)-1,4,4a,5,5a,- 6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-9-[[[(2-pyridinylmethyl)amino]acetyl]amino]2-naphthacenecarboxamide dihydrochloride; [4S-(4alpha,12aalpha)]-4-(dimethylamino)-9-[[(methylamino)acetyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro- 3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide dihydrochloride; [7S-(7alpha,10aalpha)]-N-[9-(aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,6,8,- 10a,11-pentahydroxy-5-methyl-10,12-dioxo-2-naphtha- cenyl]-α-methyl-1-pyrrolidinecarboxamide; [4S-(4alpha,12aalpha)]-9-[[[(cyclopropylmethyl)amino]- acetyl]amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11- dioxo-2-naphthacenecarboxamide; [4S-(4alpha,12aalpha)]-4-(dimethylamino)-9-[[(dimethylamino)acetyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide sulfate; [4S-(4alpha,12aalpha)]-4-(dimethylamino)-9-[[(dimethylamino)-1-oxopropyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2- naphthacenecarboxamide dihydrochloride; [4S-(4alpha,12aalpha)]-4-(dimethylamino)-9-[[(dimethylamino)-1-oxopropyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo- 2-naphthacenecarboxamide monohydrochloride; [4S-(4alpha,12aalpha)]-4-(dimethylamino)-9-[[(dimethylamino)-1-oxopropyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo- 2-naphthacenecarboxamide; [4S-(4alpha, 12aalpha)]-4-(dimethylamino)-9-[[(dimethylamino)acetyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-N-(1-pyrrolidinylmethyl)-2-naphthacenecarboxamide; [4S-(4alpha,12aalpha)]-4-(dimethylamino)-9-[[(hexylamino)acetyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2- naphthacenecarboxamide dihydrochloride; [7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2- naphthacenyl]-5-methyl-2,5-diazabicyclo[2;2;1]heptane- 2-acetamide; [7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)- 7-(dimethylamino)-5,3a,6,6a,7,10,10a,12-octahydro- 1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2- naphthacenyl]-3-methyl-4-morpholineacetamide; [7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)- 7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro- 1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2-naphthacenyl]-2-azabicyclo[2;2;1]heptane-2-acetamide; [7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)- 7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro- 1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2-naphthacenyl]-4-methyl-1-piperazinecarboxamide; [7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)- 7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro- 1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2- naphthacenyl]-4-hydroxy-1-piperazineacetamide; [7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro- 3,5,10,12,12a-pentahydroxy-6-methyl-10,12-dioxo-2- naphthacenyl]-4-methoxy-a-methyl-1-piperazinecarboxamide; [7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)- 7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro- 1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2- naphthacenyl]-4-(aminomethyl)-α-methyl-1-piperidine- acetamide; [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-1,4,4a,5,5a,- 6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl- 9-[[2-methyl-2-(methylamino)-1-oxopropyl]amino]-1,11-dioxo-2-naphthacenecarboxamide; [4S-(4alpha,12aalpha)]-4-(Dimethylamino)- 9-[[2-(dimethylamino)-2-methyl-1-oxopropyl]amino]- 1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide; [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-[[2-(dimethylamino)-3,3-dimethyl-1-oxobutyl]amino]- 1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide; [4S-(4alpha,12aalpha)]-4-(Dimethylamino)- 9-[[2-(ethylamino)-2-methyl-1-oxobutyl]amino]- 1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide; [4S-(4alpha,12aalpha)]-9-[(Aminoacetyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2- naphthacenecarboxamide; [4S-(4alpha, 12aalpha)]-9-[(L-Prolinyl)amino]-4- (dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro- 3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2- naphthacenecarboxamide; [4S-(4alpha,12aalpha)]-9-[(L-Leucyl)amino]-4- (dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro- 3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2- naphthacenecarboxamide; [4S-(4alpha,12aalpha)]-9-[(L-Tryptophanyl)amino]-4- (dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro- 3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2- naphthacenecarboxamide; [4S-(4alpha,12aalpha)]-9-[(L-Glutamyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro- 3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2- naphthacenecarboxamide; [4S-(4alpha,12aalpha)]-9-[(L-Glutaminyl)amino]-4- (dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro- 3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2- naphthacenecarboxamide; [4S-(4alpha,12aalpha)]-9-[(L-Lysyl)amino]-4- (dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro- 3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2- naphthacenecarboxamide; [4S-(4alpha,12aalpha)]-9-[[L-b-(Cyclohexyl)alanyl]- amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide; [4S-(4alpha, 12aalpha)]-9-[L-(N-Methylleucyl)amino]-4- (dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro- 3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo- 2-naphthacenecarboxamide. A compound which is one of [4S-(4alpha,12aalpha)]-4-(Dimethylamino)- 1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-9-[[(methoxyamino)acetyl]amino]- 1,11-dioxo-2-naphthacenecarboxamide; [4S-(4alpha,12aalpha)]-4-(Dimethylamino)- 1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-9-[[[(phenylmethoxy)-amino]acetyl]amino]-2-naphthacenecarboxamide; [7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)- 7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro- 1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2- naphthacenyl]-4-ethyl-1H-pyrazole-1-acetamide; [4S-(4alpha, 12aalpha)]-9-[[(Cyclobutylmethylamino)- acetyl]amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a- octahydro-3,5,10,12,12a-pentahydroxy-6-methyl- 1,11-dioxo-2-naphthacenecarboxamide; [4S-(4alpha,12aalpha)]-9-[[(2-butenylamino)acetyl]-amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide; [4S-(4alpha,12aalpha)]-4-(Dimethylamino)- 1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-9-[[(hydroxyamino)acetyl]amino]- 1,11-dioxo-2-naphthacenecarboxamide; [4S-(4alpha,12aalpha)]-4-(Dimethylamino)- 1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-9-[[[methyl(phenylmethyl)amino]acetyl]amino]-2-naphthacenecarboxamide; [7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)- 7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro- 1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2- naphthacenyl]-6-methyl-2-azabicyclo[2;2;2]octane-2- acetamide; [7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)- 7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro- 1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2- naphthacenyl]-3-methyl-1-piperazinecarboxamide; [7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)- 7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro- 1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2- naphthacenyl]-3-cyclopropyltetrahydro-4H-thiazine-4-acetamide; [7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)- 7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro- 1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2- naphthacenyl]-3-ethyl-1H-pyrrole-1-acetamide; [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-9-[[(1H-imidazol-2-ylmethylamino)-acetyl]amino]-1,11-dioxo-2-naphthacenecarboxamide; [7S-(7alpha,10aalpha)]-N-[2-[[9-(Aminocarbonyl)- 7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro- 1,6,8,1 0a, 11-pentahydroxy-5-methyl-10,12-dioxo-2- naphthacenyl]amino]-2-oxoethyl]alanine; [7S-(7alpha,10aalpha)]-N-[2-[[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro-1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2- naphthacenyl]amino]-2-oxoethyl]carbamic acid 1,1- dimethylethyl ester; [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-9-[[[[(2-methylcyclopropyl)oxy]-amino]acetyl]amino]-1,11-dioxo-2-naphthacenecarboxamide; [4S-(4alpha,12aalpha)]-9-[[[(Bicyclo[2;2;2]oct- 2-yloxy)amino]acetyl]amino]-4-(dimethylamino)- 1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide; [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl- 9-[[[(3-methyl-2-butenyl)amino]acetyl]amino]-1,11- dioxo-2-naphthacenecarboxamide; [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-1,4,4a,5,5a, 6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6- methyl-9-[[[[4-[(2-methyl-1-oxopropyl)amino]phenyl]- amino]acetyl]amino]-1,11-dioxo-2-naphthacenecarboxamide; [7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)- 7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro- 1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2- naphthacenyl]-3-ethyl-1-pyrrolidineacetamide; [4S-(4alpha,12aalpha)]-4-(Dimethylamino)- 1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-9-[[2-[[(1-methyl-1H-imidazol-2-yl)-methyl]amino]-1-oxopropyl]amino]-1,11-dioxo-2-naphthacenecarboxamide; [4S-(4alpha, 12aalpha)]-9-[[2-(Dicyclopropylamino)- 1-oxopropyl]amino]-4-(dimethylamino)-1,4,4a,5,5a,6,-11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl- 1,11-dioxo-2-naphthacenecarboxamide; [7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)-7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro- 1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2- naphthacenyl]-tetrahydro-a,2-dimethyl-4H-1,4-thiazine-4-acetamide; [7S-(7alpha, 10aalpha)]-[2-[[9-(Aminocarbonyl)- 7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro- 1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2- naphthacenyl]amino]-2-oxo-1-methylethyl]carbamic acid 2-propenyl ester; [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-9-[[2-[[3-(methylsulfonyl)phenyl]- amino]-1-oxopropyl]amino]-1,11-dioxo-2-naphthacenecarboxamide; [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-1,4,4a,5,5a,- 6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl- 9-[[2-[[(3-methylcyclobutyl)oxy]amino]-1-oxobutyl]- amino]-1,11-dioxo-2-naphthacenecarboxamide hydrobromide; [4S-(4alpha, 12aalpha)]-9-[[2-[(1,1-dimethylethyl)- methylamino]-1-oxobutyl]amino]-4-(dimethylamino)- 1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide; [7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)- 7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro- 1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2- naphthacenyl]-a-ethyl-4-methyl-2-isoxazolidineacetamide; [7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)- 7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro- 1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2- naphthacenyl]-a-ethyl-3-methyl-4H-1,2,4-triazole-4- acetamide; [4S-(4alpha,12aalpha)]-4-(Dimethylamino)- 9-[[2-(dimethylamino)-3-hydroxy-1-oxopropyl]amino]- 1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide; [7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)- 7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro- 1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2- naphthacenyl]-a-(hydroxymethyl)-4-methyl-1H-imidazole-1-acetamide; [4S-(4alpha,12aalpha)]-9-[[2-(Diethylamino)- 3-mercapto-1-oxopropyl]amino]-4-(dimethylamino)- 1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methy]-1,11-dioxo-2-naphthacenecarboxamide; [7S-(7alpha,10aalpha)]-N-[9-(Aminocarbonyl)- 7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro- 1,6,8,10a,11-pentahydroxy-5-methyl-10-12-dioxo-2- naphthacenyl]-a-(mercaptomethyl)-1-piperazineacetamide; [7S-(7alpha,10aalpha]-4-[[9-(Aminocarbonyl)- 7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro- 1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2- naphthacenyl]amino]-3-(hexylamino)-4-oxobutanoic acid; [7S-(7alpha,10aalpha)]-4-[[9-(Aminocarbonyl)- 7-(dimethylamino)-5,5a-6,6a,7,10,10a,12-octahydro- 1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2-naphthacenyl]amino]tetrahydro-6-(hydroxymethyl)- 2H-1,2-isoxazine-2-propanoic acid; [7S-(7alpha,10aalpha)]-4-[[9-(Aminocarbonyl)- 7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro- 1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2- naphthacenyl]amino]-3-[ethyl(phenylmethyl)amino]-4- oxobutanoic acid; [7S-(7alpha,10aalpha)]-5-[[9-(Aminocarbonyl)- 7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro- 1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2- naphthacenyl]amino]-4-(cyclopropylamino)-5-oxopentanoic acid; [4S-(4alpha,12aalpha)]-4-(Dimethylamino)- 9-[[2-(dimethylamino)-2-phenylacetyl]amino]- 1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1-11-dioxo-2-naphthacenecarboxamide; [4S-(4alpha,12aalpha)]-9-[[(Butylamino)(4-hydroxy- phenyl)acetyl]amino]-4-(dimethylamino)-1,4,4a,5,5a,- 6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl- 1,11-dioxo-2-naphthacenecarboxamide; [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-[2-(dimethylamino)-2-(4-methoxyphenyl)acetyl]-1,4,4a,5,5a,-6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl- 1-11-dioxo-2-naphthacenecarboxamide; [4S-(4alpha,12aalpha)]-4-(Dimethylamino)-9-[[2- (ethylmethylamino)-3-[4-(trifluoromethyl)phenyl]- acetyl]amino]-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,-12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide; [4S-(4alpha,12aalpha)]-4-(Dimethylamino)- 9-[[[4-(dimethylamino)phenyl](2-propenylamino)acetyl]- amino]-1,4,4a,5,5a,6,11,12a-octabydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide; [4S-(4alpha,12aalpha)]-9-[(D-Phenylalanyl)amino]-4- (dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro- 3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2- naphthacenecarboxamide; [4S-(4alpha,12aalpha)]-9-[(L-Phenylalanyl)amino]-4- (dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro- 3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2- naphthacenecarboxamide; [4S-(4alpha,12aalpha)]-9-[(L-Tyrosinyl)amino]-4- (dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro- 3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2- naphthacenecarboxamide; [4S-(4alpha,12aalpha)]-9-[(L-(N,N-Dimethylphenyl- alanyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a- octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11- dioxo-2-naphthacenecarboxamide; [4S-(4alpha,12aalpha)-9-[(L-Aspartyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide. A compound according to Claim 2, [4S-(4alpha,12aalpha)]-9-[(bromoacetyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide; [4S-(4alpha,12aalpha)]-9-[(chloroacetyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide monohydrochloride; [4S-(4alpha,12aalpha)]-9-[(bromoacetyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacene- carboxamide monohydrobromide; [4S-(4alpha,12aalpha)]-9-[(bromoacetyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacene- carboxamide monosulfate; [4S-(4alpha,12aalpha)]-9-[(2-bromo-1-oxopropyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5, 10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide monohydrobromide; [4S-(4alpha,12aalpha)]-9-[(2-Bromo-2-methyl- 1-oxopropyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,- 12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl- 1,11-dioxo-2-naphthacenecarboxamide hydrobromide; [4S-(4alpha,12aalpha)]-9-[(2-Bromo-1-oxobutyl)amino]- 4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro- 3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2- naphthacenecarboxamide hydrobromide; [4S-(4alpha, 12aalpha)]-9-[(2-Bromo-1-oxopentyl)amino]- 4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro- 3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2- naphthacenecarboxamide hydrobromide; [4S-(4alpha,12aalpha)]-9-[(2-Bromo-2-methyl-1-oxobutyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide hydrobromide; A compound which is one of: [4S-(4alpha, 12aalpha)]-9-[(2-Bromo-3-hydroxy-1- oxopropyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,- 12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl- 1,11-dioxo-2-naphthacenecarboxamide hydrobromide; [4S-(4alpha,12aalpha)]-9-[(2-Bromo-3-mercapto- 1-oxopropyl)amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide hydrobromide; [7S-(7alpha,10aalpha)]-4-[[9-(Aminocarbonyl)- 7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro- 1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2- naphthacenyl]amino]-3-bromo-4-oxobutanoic acid hydrobromide; [7S-(7alpha,10aalpha)]-5-[[9-(Aminocarbonyl)- 7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro- 1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2- naphthacenyl]amino]-4-bromo-5-oxopentanoic acid hydrobromide; [4S-(4alpha,12aalpha)]-9-[(Bromophenylacetyl)amino]- 4-(dimethylamino)-1,4,4a,5,5a,6,11,12a-octahydro- 3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2- naphthacenecarboxamide hydrobromide; [4S-(4alpha,12aalpha)]-9-[[Bromo(4-hydroxyphenyl)- acetyl]amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a- octahydro-3,5,10,12,12a-pentahydroxy-6-methyl- 1,11-dioxo-2-naphthacenecarboxamide hydrobromide; [4S-(4alpha,12aalpha)]-9-[[Bromo(4-methoxyphenyl)- acetyl]amino]-4-(dimethylamino)-1,4,4a,5,5a,6,11,12a- octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo-2-naphthacenecarboxamide hydrobromide; [4S-(4alpha,12aalpha)]-9-[[Bromo[4-(trifluoromethyl)-phenyl]acetyl]amino]-4-(dimethylamino)-1,4,4a,5,5a,6,- 11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl- 1,11-dioxo-2-naphthacenecarboxamide hydrobromide; [4S-(4alpha,12aalpha)]-9-[[Bromo[4-(dimethylamino)-phenyl]acetyl]amino]-4-(dimethylamino)-1,4,4a,5,5a,6,-11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl- 1,11-dioxo-2-naphthacenecarboxamide hydrobromide; [7S-(7alpha,10aalpha)]-N-[2-[[9-(Aminocarbonyl)- 7-(dimethylamino)-5,5a,6,6a,7,10,10a,12-octahydro- 1,6,8,10a,11-pentahydroxy-5-methyl-10,12-dioxo-2- naphthacenyl]amino]-2-oxoethyl]carbamic acid 1,1-dimethylethyl ester. A method of producing a compound, or its organic and inorganic salt or metal complex, of the formula: according to Claim 1, which comprises reacting a 9-[(haloacyl)amido]-5-hydroxy-6-(substituted)-6- deoxytetracycline, or its organic and inorganic salt or metal complex, of the formula: according to Claim 2, with a nucleophile of the formula WH, wherein W is as defined in Claim 1, in a polar-aprotic solvent and in an inert atmosphere. A method of producing a compound, or its organic and inorganic salt or metal complex, of the formula: according to Claim 2, which comprises reacting 9-amino-5-hydroxy-6-substituted-6-deoxytetracycline, or its organic and inorganic salt or metal complex, of the formula: with a straight or branched haloacyl halide of the formula: wherein Y, R, R 1 and R 2 are as defined in Claim 2 and Q is halogen selected from bromine, chloride, iodine and fluorine, in an inert solvent in a polar-aprotic solvent and in the presence of a base. A method of producing a compound, or its organic and inorganic salt or metal complex, of the formula: according to Claim 1, which comprises reacting a 9-amino-5-hydroxy-6-substituted-6-deoxytetracycline, or its organic and inorganic salt or metal complex, of the formula: with an acid chloride of the formula: wherein R, R 1 , R 2 and W are as defined in Claim 1 and X is halogen selected from bromine, chlorine, iodine and fluorine, in an inert solvent in a polar-aprotic solvent and in the presence of a base. A pharmaceutical composition of matter comprising a pharmacologically efective amount of a compound according to Claim 1 in association with a pharmaceutically acceptable carrier. A compound according to any one of claims 1, 3, 4 or 5 for use as a medicament. Use of a compound according to any one of claims 1, 3, 4 or 5 in the manufacture of a medicament for the treatment of bacterial infections in warm-blooded animals.

Inventors: BARDEN TIMOTHY CLAUDE, BUCKWALTER BRIAN LEE, LEE VING JICK, BARDEN, TIMOTHY CLAUDE, BUCKWALTER, BRIAN LEE, LEE, VING JICK
Applicants: WYETH CORP, WYETH HOLDINGS CORPORATION
Application year: 1994
Main classification: C07C237
IPC codes: A61K31, C07D209, C07D207, C07C239, C07D487, C07D233, C07D249, C07D333, C07D221, C07C317, C07D265, C07D213, C07C237, C07D279, C07D295, C07D521, C07D241, C07D263, C07D231, C07D211, C07C271, C07D453, C07C323, A61P31, C07D261